Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank

David M Howard,Niamh M Ryan,Reka Nagy,Alison D Murray,Toni-Kim Clarke,David J Porteous,Blair H Smith,Jonathan D Hafferty,Mark J Adams,Kathryn L Evans,Yanni Zeng,Caroline Hayward,Andrew M Mcintosh,Pippa A Thomson,Lynsey S Hall,Ian J Deary,Chris S Haley

doi:10.1038/s41398-017-0010-9

Abstract

Genome-wide association studies using genotype data have had limited success in the identification of variants associated with major depressive disorder (MDD). Haplotype data provide an alternative method for detecting associations between variants in weak linkage disequilibrium with genotyped variants and a given trait of interest. A genome-wide haplotype association study for MDD was undertaken utilising a family-based population cohort, Generation Scotland: Scottish Family Health Study (n = 18,773), as a discovery cohort with UK Biobank used as a population-based replication cohort (n = 25,035). Fine mapping of haplotype boundaries was used to account for overlapping haplotypes potentially tagging the same causal variant. Within the discovery cohort, two haplotypes exceeded genome-wide significance (P < 5 × 10−8) for an association with MDD. One of these haplotypes was nominally significant in the replication cohort (P < 0.05) and was located in 6q21, a region which has been previously associated with bipolar disorder, a psychiatric disorder that is phenotypically and genetically correlated with MDD. Several haplotypes with P < 10−7 in the discovery cohort were located within gene coding regions associated with diseases that are comorbid with MDD. Using such haplotypes to highlight regions for sequencing may lead to the identification of the underlying causal variants.

Highlights

Major depressive disorder (MDD) is a complex and clinically heterogeneous condition with core symptoms of low mood and/or anhedonia over a period of at least two weeks
Haplotype-based analysis may help improve the detection of causal genetic variants as, unlike single Single-nucleotide polymorphism (SNP)-based analysis, it is possible to assign the strand of sequence variants and combine information from multiple SNPs to identify rarer causal variants
Two haplotypes exceeded genome-wide significance (P < 5 × 10−8) for an association with MDD, one located on chromosome 6 and the other located on chromosome 10

Summary

Introduction

Major depressive disorder (MDD) is a complex and clinically heterogeneous condition with core symptoms of low mood and/or anhedonia over a period of at least two weeks. MDD is frequently comorbid with other clinical conditions, such as cardiovascular disease[1], cancer[2] and inflammatory diseases[3]. This complexity and comorbidity suggests heterogeneity of aetiology and may explain why there has been limited success in identifying causal genetic variants[4,5,6,7], despite heritability estimates ranging from 28 to 37%8,9. Haplotype-based analysis may help improve the detection of causal genetic variants as, unlike single SNP-based analysis, it is possible to assign the strand of sequence variants and combine information from multiple SNPs to identify rarer causal variants. A haplotype-based association analysis was conducted using MDD as a Howard et al Translational Psychiatry (2017)7:1263 phenotype, followed by additional fine mapping of haplotype boundaries with a replication and meta-analysis performed using the UK Biobank cohort[14]

Methods

Results

Discussion

Conclusion